Novel Methods for N- and O- Atom Transfer to Small Molecules

Novel Methods for N- and O–Atom Transfer to Small MoleculesbyDavid FisherNitrogen and oxygen are ubiquitous in natural products, pharmaceuticals, polymers, anddyes. As a result, the development of new methods for C–N and C–O bond formation is a majorfocus for synthetic organic chemists. Several new strategies for the installation of N- and O atomsin organic molecules are described herein.4-Hydroxycyclopentenones are important building blocks for the synthesis ofprostaglandins and other biologically active molecules and natural products. In 1976, GiovanniPiancatelli discovered that 2-furylcarbinols could be converted to trans-4-hydroxycyclopentenones via an acid-catalyzed cascade reaction involving a thermal 4πviiielectrocyclization. This process is known today as the Piancatelli rearrangement and remainsamong the most efficient methods for the synthesis of 4-hydroxycyclopentenones. Despite thesignificance of this approach, it can be limited by high catalyst loadings, harsh reactionconditions, and unavoidable isomerization to the thermodynamic product. We have developed ageneral, mild, dysprosium (III) trifluoromethanesulfonate-catalyzed rearrangement that providesexclusive access to either 4-hydroxycyclopentenone isomer.Nitrosoarenes typically serve as 2π synthons in transformations such as the aldol, DielsAlder,and ene reactions. Despite being efficient spin trapping agents, arylnitrosos have not beenutilized in single electron transfer processes as a tool in organic synthesis. In polymer chemistry,alkyl radical additions with nitroso compounds are used in a process known as radical trapassistedatom transfer radical coupling (RTA-ATRC) to stitch together polymer chains for thesynthesis of alkoxyamine-linked diblock copolymers. We have developed this concept as asynthetic tool in small molecule organic chemistry.Recently, we reported a mild, catalytic method for the synthesis of hindered a-aminocarbonyl compounds utilizing radical additions with in situ-generated nitroso compounds. Theprocess is redox neutral, uses catalytic CuCl2 to simultaneously generate the reactiveintermediates, occurs at room temperature and has a high degree of functional groupcompatibility. Additionally, a three component coupling reaction for the synthesis of hinderedanilines was developed by merging radical chemistry with nitroso compounds. This processutilizes commercially available starting materials and forms two C–N bonds in one pot. Finally,an intramolecular approach for the synthesis of amino alcohols is reported. This strategyprovides spatial control over the N– and O–atom transfer event in the reaction with bis-alkylhalides